Influenza is a highly contagious, acute respiratory disease that affects people of all ages. Flu viruses can be subdivided into three types, influenza A, B, and C. Of the three influenza types, influenza A and B have historically been responsible for influenza epidemics (Horimoto and Kawaoka (2001) Clin. Microbiol. Rev. 14:129-149; Zambon (1999) J. Antimicrob. Chemother. 44 Suppl B:3-9). Type A viruses are able to infect a wide variety of warm-blooded animal species including humans, pigs, horses, sea mammals, mustelids and birds. In contrast, type B and C viruses are mostly confined to humans.
The genomes of flu viruses consist of negative sense single-stranded RNA. The influenza genome is segmented and consists of seven or eight fragments of RNA encoding approximately 14 proteins (Horimoto and Kawaoka, supra; Zambon, supra). Influenza A virus contains eight segments of negative stranded RNA, including segment 8, which encodes two proteins, a nonstructural protein 1 (NS1) and a nonstructural protein 2, also referred to as nuclear export protein, (NS2/NEP) (Lamb et al. (1989) Proc. Natl. Acad. Sci. USA 76:4908-4912). The NS1 protein of all naturally occurring influenza A viruses is about 230 amino acids in length and is expressed at high levels in infected cells. NS1 is a multifunctional protein comprising two functional domains: an RNA binding domain near the N-terminus and an effector domain at the C-terminus (Qian et al. (1994) J. Virol. 68:2433-2441). The RNA binding activity of NS1 is associated with its ability to inhibit cellular pre-mRNA splicing (Fortes et al. (1994) EMBO J. 13:704-712; Lu et al. (1994) Genes Dev 8:1817-1828; Qiu et al. (1995) RNA 1:304-316). NS1 also acts as an antagonist of host immune responses. NS1 counteracts cellular interferon-α/β functions (Garcia-Sastre et al. (1998) Virology 252:324-330) by inhibiting the activation of protein kinase R (PKR) (Hatada et al. (1999) J. Virol. 73:2425-2433; Lu et al. (1995) Virology 214:222-228) and transcription factors, such as NF-κB, IRF-3 and IRF-7 (Talon et al. (2000) J. Virol. 74:7989-7996; Wang et al. (2000) J. Virol. 74:11566-11573). Within the effector domain of NS1 are two binding sites for cellular proteins. A binding site for cleavage and polyadenylation specificity factor (CPSF) is positioned around amino acid 186 and a poly(A)-binding protein II (PABII) binding site is located in the region from residues 223-237 (Li et al. (2001) RNA 7:920-931). These binding sites are required for the inhibition of 3′-end processing of cellular pre-mRNAs, and are important for influenza virus replication (Noah et al. (2003) Virology 307:386-395).
Each year, numerous individuals are infected with different strains and types of influenza virus. Infants, the elderly, those without adequate health care, and immuno-compromised individuals are especially at risk of dying from such infections. Compounding the problem is the rapid evolution of novel influenza virus strains that spread amongst various species, thereby necessitating the continuous production of new vaccines.
Thus, there remains a need for the development of effective strategies for the treatment and prevention of influenza infection.